α,α,α-Trifluorothymidine (FTD, see the structural formula below) is a nucleoside analogue with substitution of a methyl group to trifluoromethyl group at the 5-position of thymidine, which was synthesized by Heidelberger et al. (J. Am. Chem. Soc., 84: 3597-3598, 1962; J. Med. Chem., 7: 1-5, 1964).

Unlike a fluorouracil (FU)-based antitumor drug that are widely used for cancer patients, FTD has no effect on RNA, and is phosphorylated by an intracellular thymidine kinase to form a monophosphorylated form, namely, trifluorothymidine monophosphate (F3TMP). The F3TMP binds to a thymidylate synthase (TS) to exhibit a DNA synthesis-inhibiting effect (Biochemistry, 33: 15086-15094, 1994; Mol. Pharmacol., 1: 14-30, 1965). FU-based antitumor drug such as 5-FU that are clinically used as a representative antitumor drug have been reported to show a inhibition of TS activity as the main mechanism of action, while it has recently been reported that some patients are less sensitive to the FU-based antitumor agent (J. Clin. Oncol., 12: 2640-2647, 1994; Id. 14: 176-182, 1996; Id. 21: 815-819, 2003). The incorporation of FTD into DNA may represent an antitumor activity to FU less sensitive pacients by different mechanism of action from FU-based antitumor drug. Clinical trials of FTD were performed in 1970s, revealing the problem inherent in FTD that this drug is degraded by a thymidine phosphorylase (TP) in a human body after intravenous administration, resulting in the extremely shortened half-life thereof in the blood, i.e. approximately 12 minutes (Cancer Res., 32: 247-253, 1972). Further, although some tumor regressions were noted by divided doses every three hours, several problems have been also indicated that this means of administration lacks general usage, have showed adverse invent of the bone marrow supression and gastrointentinal toxicities, and have not necessarily been able to contribute to survival period even in some patients having tumor shrinkage (Cancer Chemother. Rep., 55: 205-208, 1971).
Under the circumstances, the applicant has discovered 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride (see the structural formula below), a thymidine phosphorylase inhibitor (TPI) for preventing FTD degradation, which enables the blood concentration of FTD to be maintained and the drug to be administered orally for improving the general usage, and has developed a anticancer drug (TAS-102) containing FTD and TPI in a molar ratio of 1:0.5 (Japanese Patent No. 3,088,757; International Journal of Oncology 25: 571-578, 2004).

A phase I clinical trial of the combination drug was carried out in USA, starting by once-a-day oral dosing, to confirm that the blood FTD concentration was maintained and thus the combination drug is susceptible of oral administration. However, the resultant therapeutic effect of this combination drug against cancer was not satisfactory in the trial.